***************************************
A ProMED-mail post
<http://www.promedmail.org>
ProMED-mail is a program of the
International Society for Infectious Diseases
<http://www.isid.org>
[The original report of the human rabies case
that occurred in Brazil and has survived after
the use of the "Milwaukee protocol" (a protocol
that was associated with survival of a teenaged
girl in Milwaukee, Wisconsin, USA several years
ago) was carried on the ProMED-PORT list (a
ProMED-like system in Portuguese with a focus on
events in Brazil, elsewhere in Latin America and
in Portuguese speaking Africa) and later
reproduced on the general ProMED-mail list. In
response to this, Dr. Thiravat Hemachudha and Dr.
Henry Wilde both from Chulalongkorn University in
Bangkok were contacted and raised questions for
the Brazilian team. In response to this, they
shared their experiences and comments, based on
their experience in Thailand with treating human
rabies cases, and their use of the Milwaukee
protocol. PRO/MBDS feels this presentation is
important to share with the PRO/MBDS network, and
the reports are included below. - Mod.MPP]
In this posting:
[1] ProMED-mail posting on the original report of
Brazilian human rabies survivor
[2] Brazilian case, follow-up questions and answers
[3] Thailand comparison and comment
[4] Thailand additional comments
******
[1] ProMED-mail posting on the original report of
Brazilian human rabies survivor
Date: Tue 11 Nov 2008
Source: Ministerio da Saude, Secrearia de
Vigilancia em Saude, Directoria de Vigilancia
Epidemiologica, Coordinacao Geral de Doencas
Trannsmissiveis, Coordinacao de Vigilancia da
Doencias Transmitidas por Vetores e
Antropozoonoses [in Portuguese, trans. Mod. TY, edited]
[Ministry of Health, Department of Disease
Surveillance, Directorate of Epidemiologic
Surveillance, General Coordination for
Communicable Disease, Coordination from
Surveillance of Vectorborne and Anthropzoonotic Diseases - Trans.by Mod.MPP]
<http://portal.saude.gov.br/portal/arquivos/pdf/nota_tecnica_raiva_humana_11_08.pdf>
Technical Note: Treatment of cases of human rabies in Floresta Pernambuco
-------------------------------------------------------------------------
On 14 Oct 2008, the Department of Epidemiological
Surveillance (DES), Department of Health
Surveillance, Ministry of Health (MOH), through
the state Department of Health of Pernambuco, was
notified of a suspected case of human rabies from
the municipality of Floresta. The epidemiological
investigation was initiated by Epidemiological
Surveillance of the city, together with the Pernambuco Department of Health.
This [case] is a boy of 15 years, with report of
aggressive attack by a hematophagous bat and the
initiation of symptoms on 6 Oct 2008, who was
then transferred to the University Hospital
Osvaldo Cruz of the University of Pernambuco on
10 Oct 2008. The patient received 4 doses of
vaccine against rabies before the start of
symptoms [the USA CDC recommends 5 doses of
vaccine post-exposure. - Mod.TY]. The incubation
period was approximately 29 days.
A hair follicle biopsy of the region of the nape
of the neck was submitted for reverse
transcription polymerase chain reaction (RT-PCR),
nested PCR and genetic sequencing, carried out by
the Pasteur Institute-SP Laboratory. On 22 Oct
2008, the tests were positive for rabies [virus],
which was identified as a variant compatible with
[rabies virus] isolates from _Desmodus rotundus_ [vampire] bats.
The patient was transferred to the intensive care
unit on 11 Oct [2008], and on 13 Oct [2008] was
intubated and the Milwaukee treatment protocol
was initiated, which was used in a patient with
rabies in 2004 in the United States. On 30 Oct
[2008], he was brought out of the induced coma
and today [11 Nov 2008] the patient is unsedated and is clinically stable.
Specific tests for titration of enzymes, which
will be processed in the United States, will be
provided to the DES/MOH and medicines not available in Brazil will be imported.
The successful outcome of this patient, as well
as the cure observed in the patient in the United
States, opens rather promising prospects [for
treatment of] this disease, which so far is
considered to have a case fatality rate of 100
percent. In facing this possibility, the DES /
MOH will prepare a treatment protocol to be used
in other cases of human rabies in Brazil.
--
Communicated by:
ProMED-PORT
<promed@promedmail.org>
[Survival in children who received treatment with
[rabies-immune] serum or immunoglobulin before
the onset of symptoms is well recognized. There
are several (not many) cases reported in the literature.
The factors that lead to survival are not well
known, however, passive and active immunization,
above a certain age seem to be important determinants.
As far as I know, this is the 1st documented case
[of rabies survival] in Brazil. Rabies should
still be considered a uniformly fatal disease,
and a few cases in among thousands [of
fatalities] does not mean that the disease can be
cured. - Mod.LJS (Mod LJS is the ProMED-PORT moderator - Mod.MPP)]
[The physicians who implemented the Milwaukee
rabies treatment protocol that was successful in
the case of the 15-year-old girl indicated that
induction of coma and control of cerebral edema
and generalized cerebral artery spasm were
critical elements in the patient's survival.
Survival was prolonged enough for the patient to
develop high-titered antirabies antibody in both
blood and CSF (see ProMED archives listed below).
The above report does not provide enough details
about the treatment to know how closely the Milwaukee protocol was followed.
References:
-----------
Willoughby RE Jr, Tieves KS, Hoffman GM, Ghanayem
NS, Amlie-Lefond CM, Schwabe MJ, Chusid MJ,
Rupprecht CE. 2005. Survival after treatment of
rabies with induction of coma. N Engl J Med 352(24): 2508-14.
Willoughby RE, Roy-Burman A, Martin KW,
Christensen JC, Westenkirschner DF, Fleck JD,
Glaser C, Hyland K, Rupprecht CE. 2006. Neurol Res 28(7):730-7.
Hu WT, Willoughby RE Jr, Dhonau H, Mack KJ. 2007.
Long-term follow-up after treatment of rabies by
induction of coma. N Engl J Med 357(9):945-6.
A map of Brazil showing the location of
Pernambuco state in the east can be accessed at
<http://www.lib.utexas.edu/maps/americas/brazil.jpg>
A HealthMAP/ProMED interactive map of Brazil can
be accessed at
<http://healthmap.org/promed/en?v=-10.8,-53.1,4>.
- Mod.TY (Mod. TY is one of the ProMED-mail viral
disease moderators. - Mod.MPP)]
******
[2] Brazilian case, follow-up questions and answers
Date: Thu 21 Nov 2008
From: Dr. Gustavo Trinidade Henriques Filho <gustavothf@uol.com.br>
[ProMED received questions and comments from
several subscribers. The questions were combined
and Dr. Gustavo Henriques, the physician in
charge of the surviving rabies case, kindly replied. - Mod. TY]
1). Did the patient develop anti-rabies antibody
in blood and CSF? If so, at what stage of his
infection were antibodies first detected?
Yes, neutralizing antibodies were detected in the
laboratory of Dr. Ivanete Koteit at the Pasteur Institute, São Paulo, Brasil.
The titers increased dramatically over the
treatment period, exceeding 100 IU/mL in both serum and CSF.
2). Was rabies virus RNA detected in CSF?
No. Virus RNA was detected in skin (hair follicle).
3). Was the virus isolated and sequenced?
Yes.
4). Was rabies-immune globulin administered to the patient at any time?
No, unfortunately the patient only received
tissue culture-based vaccine. Full prophylaxis was not given.
5). How long after the vampire bat bite was the
first dose of rabies vaccine administered?
4 days.
6). Was a 5th dose of vaccine administered (after symptoms appeared)?
Unfortunately yes.
7). Since the patient received 4 doses of rabies
vaccine before the first symptoms appeared, do
you consider this to be a case of vaccine
failure?
Immunoglobulin was not given, which explains the failure of the prophylaxis.
8). Was the Wisconsin protocol followed exactly, or were changes made?
We followed the "Milwaukee protocol" as closely
as we could. We used ketamine, midazolan and amantadine.
We did not use ribavirin, which is the
recommendation of version 2 of the protocol. We
did not use an EEG due to limited availability.
9). Did the patient have cerebral edema? A
neurologist in Thailand wrote to say that of the
several rabies patients that he has attended,
cerebral edema was not a problem.
MRI findings included edema of the deep gray
matter. There was no need to treat cerebral edema clinically.
We are delighted to report our survivor, and will
follow up with submission of a detailed
manuscript very quickly, so that others can achieve similar successes.
Please send me copies of the articles that you
[ProMED subscribers and others] discuss our case,
at the following address and e-mail.
--
Communicated by:
Gustavo Trindade Henriques Filho
Critical Care Unit of Infectious Disease
Oswaldo Cruz University Hospital
Recife-Pernambuco, Brasil.
Adress: Rua do Futuro, 1200/3301 Gracas
Recife-Pernambuco, Brasil
CEP: 52.050-010
gustavothf@uol.com.br>
[ProMED is grateful to Dr. Henriques for his
prompt response. Questions above were provided
by Drs. Henry Wilde, Bangkok, Thailand, Allen
Lenoir, Miami Florida, USA, Nancy N. Bermal,
Muntinlupa City, Philippines, and Mod. TY]
******
[3] Thailand comparison and comment
Date: Mon 17 Nov 2008
From: Thiravat Hemachudha <fmedthm@gmail.com>
It is interesting to see the eventual outcome of
this Brazilian case. Approximately 5 weeks after
onset, he became clinically stable, could open
his eyes. He received therapeutic coma and
antiviral 7 days after the onset. Viral RNA could
be demonstrated in hair follicles and saliva,
however, status of antibodies in the serum and CSF were not reported.
Several factors responsible for survival may include:
1. Nature of virus variant. As seen in cases
with good recovery, all were associated with bat
variants; 1972 and 2004 US cases and (hopefully) 2008 Brazilian case
2. Absence of classic manifestations. 1972 US
case had unsteady gait, dysarthria and
hemiparesis 4 days after onset; 1976 dog variant
case had quadriparesis, myoclonus, ataxia,
dysmetria, dysdiadokokinesia, frontal lobe
dysfunctions, bi-brachial weakness; the remaining
(1977 laboratory accident case, one 1994 and two
1995 Mexican cases related to dog variants and
one Indian related to dog variant in 2003) also
had no typical features of rabies. This may also
include 2004 US and 2008 Brazilian.
It is understandable that bat related cases may
have atypical presentations since at least some
bat variants have different tissue tropism (skin
and dermis cells rather than nicotinic
acetylcholine receptor at the muscle), thus, may
use different neural pathways. However, in the
remaining dog related cases, this is still
intriguing. Having atypical clinical signs in dog
cases may reflect interaction between host
factors and virus spread, resulting to a more favorable outcome.
3. Early development of serum and CSF
neutralizing antibody. This may best explain the
1972 and 2004 US cases. These two also did not
have virus recovered or RNA demonstrated.
Nevertheless, this may not be the sole
determinant since 2002 Indian case had CSF
appeared in both compartments as early as day 8
after onset (2004 US had antibody on day 6).
Whether or not presence of virus or viral RNA in
the secretions is a bad prognostic factor remains
to be determined (depending on the outcome of this Brazilian case).
4. Postexposure treatment after symptoms
developed may not be a contraindication. 1972 and
1976 bat cases, and the remaining cases (lab
accident and dog related) either had pre- or post exposure treatment.
What previously believed as immune accelerated
deaths may not be true. We have shown that
furious rabies patients who died faster had more
cell mediated immune (CMI) response to rabies
antigen as well as more cytokine responses (as
determined in the blood) when compared to
paralytic rabies. We proposed this as evidence of
bad immune effect. However, our recent study in
furious and paralytic rabies infected dogs
revealed that furious dogs had more viral load in
the brain but less cytokine response (RNA
transcripts) and less brain MRI disturbances than
paralytic dogs. Virus in the brain then would be
drained into the cervical lymph nodes, explaining
more CMI response in the blood of furious rabies.
The only concern about immune hazard may be the
use of rabies immune globulin. We have treated a
furious rabies patient with large dose of
intravenous rabies immune globulin. This caused
paralytic complications, probably by immune attack against virus in the axon.
5. Therapeutic coma induction. At present, it
is still inconclusive whether survival is due to
the effect of treatment. Longer survival in
treated cases may also be a misunderstanding.
Generally, treatment with intensive care support
was withheld once there were no signs of brain
functions. In cases with therapeutic coma, this
supportive care was prolonged. Autopsy in our
case treated with such protocol revealed
liquefied brain tissue at autopsy (similar to others with same treatment).
Finally, it has been known that virus enters the
brain and spinal cord long before the symptoms
developed. This is based on MRI and
electrophysiologic evidence in rabies patients at
various stages. Once the death cascade starts, it
may not be possible to stop the progression
unless counteractive mechanisms have been
developed more or less at the same stage (such as
development of antibody) which may depend in part
of the nature of virus variant. To date, there
has been no experimental or animal evidence
supporting the role of excitotoxicity in rabies.
Antiviral, ribavirin, cannot penetrate the blood
brain barrier, however, it may help fighting
against virus in the peripheral tissue. Regarding
brain edema, we have never seen brain edema at
autopsy except in our case who was treated with
massive dose of rabies antibody.
References:
1. Hemachudha T, Phanuphak P, Sriwanthana B,
Manutsathit S, Phanthumchinda K, Siriprasomsup W,
Ukachoke C, Rasameechan S, Kaoroptham S.
Immunologic study of human encephalitic and
paralytic rabies. A preliminary study of 16 patients. Am J Med 1988;84:673-6.
2. Hemachudha T. Chapter on Rabies. In: Vinken
PJ, Bruyn GW, Klawans HL, eds Handbook of
clinical neurology. Viral Disease. Amsterdam:
Elsevier Science Publishers, 1989:383-404.
3. Hemachudha T, Panpanich T, Manatsathit S,
Phanuphak P. Immune activation in human rabies.
Trans Royal Soc Trop Med Hyg 1993;87:106-8.
4. Hemachudha T. Human Rabies: Clinical
aspects, pathogenesis and potential therapy. In:
Rupprecht CE, Koprowski H, eds. Current Topics in
Microbiology and Immunology. Lyssavirus. Springer Verlag 1994:121-43.
5. Hemachudha T, Laothamathas J, Rupprecht
CE. Rabies. Lancet Neurology 2002; 1:101-9.
6. Laothamatas J, Hemachudha T, Mitrabhakdi
E, Tulyadaechanont S, . MR imaging in human
encephalitic and paralytic rabies. Am J Neuroradiology 2003; 24:1102-9.
7. Hemachudha T , Sunsaneewitayakul B,
Mitrabhakdi E, Suankratay C, Laothamathas J,
Wacharapluesadee S, Khawplod P, Wilde H.
Paralytic complications following intravenous
rabies immune globulin treatment in a patient
with furious rabies. Int J Infect Dis 2003:7:76-7.
8. Hemachudha T, Wacharapluesadee S,
Lumlertdaecha B, Orciari LA, Rupprecht
CE, La-ongpant M, Juntrakul S, Denduangboripant
J . Sequence analysis of rabies virus in humans
exhibiting furious or paralytic rabies. J Infect Dis 2003; 188:960-6.
9. Hemachudha T, Wacharapluesadee S,
Mitrabhakdi E, Wilde H, Morimoto K, Lewis RA.
Pathophysiology of human paralytic rabies. J Neurovirol 2005;11:93-100.
10.Mitrabhakdi E, Shungshoti S, Wannakrairot P,
Susuki S, Laothamatas J, Lewis RA Hemachudha T.
Difference in neuropathogenetic mechanisms in
human encephalitic and paralytic rabies. J Neurol
Sci. 2005;238(1-2):3-10. Epub 2005 Oct 14.
11.Hemachudha T. Rabies. Current Neurology and
Neuroscience Reports. Brust JCM, Fahn F, Jubelt B
(eds), Current Science, Inc. 2006;6:460-8.
12.Hemachudha T, Sunsaneewitayskul B, Desudchit
T, Suankratay, C, Sittipunt C, Wacharapluesadee
S, Khawplod P, Wilde H, Jackson AC. Failure to
treat a rabies patient with coma induction
therapy. J Neurovirol 2006:12:407-9.
13.Laothamatas J, Wacharapluesadee S,
Lumlertdacha B, Ampawong S, Vera Tepsumethanon
V, Phumesin P, Asavaphatiboon S, Worapruekjaru
L, Hemachudha T. Canine furious and paralytic
rabies: virological, cytokines, and neuroimaging
studies. J Neurovirol 2008;14:119-129..
14.Wilde H, Hemachudha T, Jackson AC. Viewpoint:
management of human rabies. Trans R Soc Trop Med Hyg 2008 May 15
[Professor Thiravat Hemachudha added the
following, after receiving the answers to the questions in part [1] above]
Therefore, this is what we expected. Rabies
antibody was developed very early in the disease
course, if I understand correctly as what
Dr.Gustavo mentioned. This may be a critical
factor. RNA was demonstrated only in hair
follicles, unlike our case (and others) where RNA
was found with an increasing number at all sites,
CSF, urine, saliva. Viruses at other sites might
have been eradicated since the beginning in this
Brazilian case. There was no EEG monitoring. This
means that coma induction to "burst suppression"
as in Milwaukee protocol may not be that
necessary and usually it is dangerous. To achieve
such a coma stage, dosage of medications would be
large and this requires careful monitoring to
avoid complications it may induce, especially to
the cardiovascular system. Monitoring of cardiac
output, peripheral vascular resistance, wedge
pressure, etc. is necessary as in Thai case and
others (with treatment failure) once large dose
of these sedatives is used. Using such
sedatives as in the Brazilian case is relevant
and this has been done to rabies patients
elsewhere in dog rabies endemic countries for
decades with the aim to control agitated symptoms
but not to combat excitotoxic mechanisms.
Vaccine use in this case more or less suggests
that it is not contraindicated. The 1st survivor
and others had post-exposure prophylaxis. It is
hoped that this boy will not have major sequellae
which then supports that just routine intensive
care support is sufficient and what has been
expressed in "viewpoint of management of human
rabies (2008)" holds true that intensive care
support should be applied to a patient who has
antibody in the serum and in CSF at admission. To
prolong death in patients who do not have
antibody since the beginning may not be
beneficial. As in our study in rabies infected
dogs (J Neurovirol 2008), cytokine mRNA
transcripts is only a transient phenomenon in the
brain. It appears during the early stage (not
very prominent) and disappears thereafter.
--
Communicated by:
R Thiravat Hemachudha, MD
Professor of Neurology
Department of Medicine (Neurology) and
Molecular Biology Center for
Neurological Diseases
Chulalongkorn University Hospital
Bangkok, Thailand
<fmedthm@gmail.com>
******
[4] Thailand additional comments
Date: Sat 22 Nov 2008
From: Henry Wilde <wildehenry@yahoo.com>
It is great to know that there was another
survivor of rabies but keep in mind that this may
not at all be due to the chemicals or deep
anesthesia which was provided but due to good
nursing and ICU care. This case is virtually
identical to that of the 6 year old Ohio boy who
had neither antiviral chemicals nor even
intubation; only good nursing care. The Brazilian
patient had significant CNS antibodies early in
the course of his illness which is something we
have not seen in the over 100 rabies patients
that we followed in Bangkok. We infused HRIG
intravenously (900 mL total) into one patient and
found that the antibody did not appear in CNS
fluid, indicating that the BB [blood-brain]
barrier remains intact in most if not all
cases. Thus, I would assume that the antibody in
the Brazil, Wisconsin and Ohio patients were
produced in the CNS and may have played a
significant role in recovery. I stand by our
recommendation, made in the referenced paper
above [Wilde H, Hemachudha T, Jackson AC.
Viewpoint: management of human rabies. Trans R
Soc Trop Med Hyg 2008 May 15], that we would
treat any patient who is still reasonably intact
and has antibody in CNS on or shortly after
admission with high quality standard ICU care
without the Wisconsin regimen which only adds to
risks and is unlikely to contribute to recovery
or could be carried out in most locations where
rabies is common. The real issues in rabies for
today are not related to these rare recoveries
but to how we manage to control the vector: the
huge numbers of free roaming dogs in most rabies
endemic countries. We still do not have an answer
for this nor do governments have the will to tackle it.
--
Communicated by:
Henry Wilde, MD, FACP
Professor of Medicine
Division of Research Affairs
Faculty of Medicine
Chulalongkorn University
Rama IV Road, Bangkok, Thailand 10330
<wildehenry@yahoo.com>
[For background information on human rabies
survival, see the below archives available at the
general ProMED-mail website, <http://www.promedmail.org> - Mod.MPP
Rabies, human survival, bat - Brazil: (Pernambuco) 20081114.3599
2004
----
Rabies, human, bat - USA (WI)(07): recovery 20041231.3459
Rabies, human, bat - USA (WI)(06): recovery 20041223.3390
Rabies, human, bat - USA (WI)(05): recovery 20041201.3213
Rabies, human, bat - USA (WI)(04): recovery 20041129.3194
Rabies, human, bat - USA (WI)(03): recovery 20041126.3163
Rabies, human, bat - USA (WI)(02): partial recovery 20041110.3040
Rabies, human, bat - USA (WI) 20041021.2853]
....................................mpp
*##########################################################*
************************************************************
ProMED-mail makes every effort to verify the reports that
are posted, but the accuracy and completeness of the
information, and of any statements or opinions based
thereon, are not guaranteed. The reader assumes all risks in
using information posted or archived by ProMED-mail. ISID
and its associated service providers shall not be held
responsible for errors or omissions or held liable for any
damages incurred as a result of use or reliance upon posted
or archived material.
************************************************************
Become a ProMED-mail Premium Subscriber at
<http://www.isid.org/ProMEDMail_Premium.shtml>
************************************************************
Send all items for posting on the PRO/MBDS list to:
<promed-mbds@promedmail.org> (NOT to an individual
moderator). If you do not give your full name and
affiliation, it may not be posted. If you are concerned
about repercussions if your name appears on a posting,
please advise us to withhold your identifying information
when you submit a piece for posting. Send commands to
subscribe / unsubscribe, get archives, help, etc. to:
majordomo@promedmail.org. For assistance from a human being
send mail to: owner-promed@promedmail.org>
############################################################
############################################################
0 comentarios:
Publicar un comentario en la entrada